Abstract: Cancer Immunotherapy Through Intratumoral Activation of Recall Responses The overarching goal for this project is to elucidate whether recall antigen expression in the tumor microenvironment can be used to enhance cancer immunotherapy, or potentially, serve as a new anti-cancer modality. These studies will also determine whether immunological memory/pre- existing immunity against an oncolytic poliovirus, PVSRIPO, is an impediment or asset to therapy. PVSRIPO is showing remarkable promise in patients with glioblastoma, recently received Breakthrough Therapy Designation from the FDA, and represents a unique approach delivering a potent human recall antigen (polio capsid) into human tumors. Surmounting evidence indicates that recall response activation leads to both innate and adaptive inflammation, capable of inducing immune responses against new antigens. This proposal seeks to harness the power of these responses to enhance cancer immunotherapy. This will be accomplished through testing the role of pre-existing anti-polio immunity on PVSRIPO therapy in mouse models of melanoma and brain cancer in affecting both efficacy and antitumor immunity. Additionally, polio and tetanus antigens, which are recall antigens for nearly everyone in the world, will be exogenously delivered into murine melanoma and brain tumors to test if intratumoral inflammation and engagement of antitumor immunity occurs in mice with recall responses to these antigens. Lastly, an in vitro human system will be used to evaluate the effects of recall antigen induced inflammation on antigen presenting cells and priming of new T cells. These studies aim to exhaustively test the adjuvant potential of recall responses in the context of cancer immunotherapy; which has remained an unexplored route to engage antitumor immunity to date.